Creatine and the Immune System: What Science Shows So Far

Creatine Beyond Muscle

Creatine may be the most thoroughly studied supplement in sports nutrition. It sits in muscle as phosphocreatine, a rapid recharge system for ATP, the molecule cells spend whenever they need energy fast. Decades of trials have tied creatine monohydrate to gains in strength, power, and lean mass, and the International Society of Sports Nutrition calls it the most effective ergogenic supplement available for increasing high intensity exercise capacity. That reputation is why most people know creatine as a gym product and nothing more.

Kristen Drescher, PhD, an immunologist at Creighton University, thinks the gym framing misses something important. Speaking at the 2022 Creatine Conference, she laid out a case that creatine also talks to the immune system, and that this conversation has been quietly documented for decades. Her team’s written argument appears in a 2021 review in the journal Nutrients, authored with Eric Bredahl, Joan Eckerson, Steven Tracy, and Thomas McDonald. That review notes that creatine is well studied for its effects on performance and health and that it aids recovery from strenuous exercise by reducing inflammation. It also concedes a gap: because most creatine research involves young athletic adults, far less is known about its effects in children or the elderly.

This article works through Drescher’s talk, checks her main claims against the published record, and adds newer human evidence that arrived after the talk was recorded. One note on expectations before we begin. Nearly everything below comes from cells in dishes and from animal experiments, because that is where the immune story of creatine currently lives. Where Drescher speculates, we will label it speculation, and where human data pushes back, we will say so plainly.

A Rediscovered Idea From the 1970s

Drescher opens by correcting the field’s memory: the notion that creatine has immune properties is not new, it is rediscovered. In the late 1970s, the pharmacologists N. K. Khanna and B. R. Madan ran a series of inflammation experiments in rats. They injected irritating substances into the footpads of the animals. Carrageenan, a seaweed derived compound, triggers swelling within hours and models acute inflammation, while nystatin sets off a slower, more chronic process. The rats were then treated with creatine or with creatinine, the breakdown product of creatine, either by mouth or by injection. According to Drescher, both compounds reduced the swelling, and creatine held its own against some of the standard drugs of the day.

The published record supports her account. The 1978 paper reported that creatine was orally effective in every inflammation model the team used, that it relieved pain the way many nonsteroidal agents do, that it caused no stomach ulceration at effective doses, and that its potency was comparable to phenylbutazone, a widely used NSAID of that era. The 1979 companion paper found that oral creatinine suppressed inflammatory responses produced by carrageenan, serotonin, nystatin, and formaldehyde, and its authors suggested it might work partly by interfering with prostaglandins, the same chemical family targeted by aspirin and ibuprofen. Drescher finds the creatinine result the more surprising of the two, because creatinine has long been dismissed as biological waste, a molecule the kidneys filter out and doctors measure only to check kidney function.

Then the thread went cold. Creatine became a sports phenomenon in the 1990s, and its other possible roles drew little attention. Drescher’s group helped revive the question with a 2016 review titled Beyond Muscles, which argued that creatine’s effects outside the musculoskeletal system deserve far more study. The talk summarized here continues that project.

How the Immune System Detects Threats

Because most of her audience were not immunologists, Drescher builds the story from the ground up, and it helps to do the same here. She describes an immune response as running in three phases. First comes recognition, when the immune system notices a threat to the host. Then activation, when defensive proteins are produced and cells are recruited to eliminate the invader. Finally resolution, when the response winds down and repair begins. Her research concerns the first two phases.

Recognition depends on an elegant piece of evolutionary design. Cells of the innate immune system carry pattern recognition receptors, and among the best characterized are the Toll like receptors, or TLRs. A TLR fires when it touches a pathogen associated molecular pattern, or PAMP: a molecular signature such as lipopolysaccharide (LPS) from the outer coat of gram negative bacteria, flagellin from bacterial tails, or the single stranded and double stranded RNA of viruses. Drescher stresses three properties that make PAMPs ideal alarm triggers. They persist for the pathogen’s entire life. They cannot be mutated away, because losing them is lethal to the microbe. And they do not appear on vertebrate cells, so the alarm rarely misfires against the body itself.

Each TLR has a sensing domain that grabs the PAMP, a segment anchoring it in a membrane, and a signaling domain that launches the defensive cascade inside the cell. Some TLRs face outward from the cell surface, while others sit inside endosomes, internal compartments where they inspect swallowed material for viral genetic code, making them central to antiviral defense. TLRs are abundant on macrophages and dendritic cells and are most heavily expressed at the body’s common entry points for infection: the respiratory tract, the gut, and the skin. Their signaling is the earliest response a host mounts, broad rather than precise, and its main output is cytokines, the chemical messengers that mobilize the wider immune system.

One small correction is worth making here. In the talk, Drescher puts the number of human TLRs at twelve. Standard references count ten functional TLRs in humans, TLR1 through TLR10, while mice carry twelve. The slip changes nothing about the story, but an article about evidence should not repeat it.

Creatine and Toll Like Receptors

Drescher’s team asked a direct question: does creatine change how strongly cells express these alarm receptors? They used two cell systems, the RAW 264.7 mouse macrophage line and primary splenocytes taken straight from mice, the second serving as a check that any result was not an artifact of an immortalized line or of macrophages alone. They tested three substances: creatine monohydrate, the form in most supplements; creatinine, its breakdown product; and creatine ethyl ester, an alternative formulation included to learn whether the form of creatine matters.

They tracked four receptors chosen to span different classes of threat. TLR2 senses gram positive bacteria through molecules such as lipoteichoic acid. TLR3 detects double stranded RNA, a viral signature. TLR4 responds to LPS from gram negative bacteria. TLR7 recognizes single stranded RNA, another viral cue, so the panel covered both bacterial and viral sensing, at the cell surface and inside endosomes. The team measured messenger RNA across the first hour after exposure, normalized to a housekeeping gene, then confirmed the picture at the protein level with antibody staining at 24 and 48 hours.

The results were published in 2011 in International Immunopharmacology with Korey Leland as first author. Creatine monohydrate pushed down mRNA levels of all four receptors in the macrophage line, creatinine did the same, immunostaining confirmed the drop in receptor protein, and the splenocyte experiments matched the cell line. Creatine ethyl ester behaved differently. In the talk, Drescher describes it as producing a slight, nonsignificant uptick; the published paper goes further and reports that the ester form actually increased expression of all four TLRs. Either way, her broader conclusion stands: the formulation of creatine matters, and results from one form should not be assumed to apply to another.

Is turning down the body’s alarm receptors a bad thing? Drescher addresses the worry directly. The treatment does not abolish TLR expression; it lowers it temporarily, a dimmer switch rather than an off switch. For most people, she argues, this is unlikely to compromise infection sensing in any meaningful way. The more interesting implication runs the other direction. In conditions from sepsis to autoimmune disease, the problem is too much alarm signaling rather than too little, and she returns to that idea later in the talk.

TNF Alpha and the NF Kappa B Pathway

The next question was whether creatine affects not just the sensors but the products of activation. The team focused on tumor necrosis factor alpha, usually shortened to TNF alpha or simply TNF. Drescher describes it as a potent inflammatory mediator and an acute phase reactant, one of the first molecules to surge after infection alongside interleukin 1 and interleukin 6. TNF summons immune cells to the site of trouble and helps trigger the adaptive immune response, giving it a role in both fresh and ongoing infections. Its chief producers include macrophages, the tissue dwelling cells she calls the first responders of the immune system.

TNF also matters far beyond infection. A major review in Nature Reviews Rheumatology describes TNF as a pleiotropic cytokine with central roles in both normal physiology and disease, and notes that therapeutics aimed at TNF mediated diseases have been built on this biology. Rheumatoid arthritis is the classic example, where TNF blocking drugs changed the standard of care. That is why a cheap dietary compound that modestly trims TNF output would be worth understanding, and also why claims in this territory deserve extra scrutiny.

Drescher’s group ran the experiment in a deliberately demanding direction. Rather than asking whether creatine prevents inflammation, they asked whether it can reduce inflammation that already exists. They exposed mouse macrophages to LPS for 24 to 48 hours, which reliably drives TNF production up, then added creatine or creatinine. TNF staining dropped visibly, and when the team quantified staining intensity, the reduction was robust for both compounds. Control experiments showed that neither compound destabilizes existing TNF transcripts, meaning the brake operates upstream, at the level of gene activation rather than message destruction.

That pointed to NF kappa B, the master switch through which most TLR signaling flows on its way to activating cytokine genes, TNF included. In nuclear extracts from treated cells, less NF kappa B reached the nucleus, where it would normally switch those genes on. The published version of this work, a 2018 paper in the journal Cytokine, reported that creatinine hydrochloride significantly reduced TNF mRNA and protein in a human T cell line and in human and mouse macrophage lines, and that cells treated with LPS plus creatinine had significantly less TNF than cells treated with LPS alone. Related work from the lab tied the effect to reduced movement of the p65 subunit of NF kappa B into the nucleus.

Macrophages in Attack and Repair Mode

Macrophages do not have a single personality. Immunologists describe two broad activation states. M1 macrophages are the fighters: polarized by exposure to LPS, interferon gamma, and related signals, they produce inflammatory mediators such as interleukin 1 beta, interleukin 6, interleukin 12, and TNF, along with nitric oxide and reactive oxygen and nitrogen species, and they are the cells that contain infections like tuberculosis. M2 macrophages, induced by interleukin 4, handle a different portfolio: suppressing inflammation, repairing tissue, remodeling, and supporting new blood vessel growth, partly through calming signals such as interleukin 10. The states are plastic, cells can shift between them, and the balance between M1 and M2 helps determine whether an inflamed organ heals or sustains lasting damage, which is why disturbed polarization features in a range of chronic and autoimmune conditions.

Drescher’s lab did not test polarization, but another group did, and their study, published in Immunity in 2019 by Liangliang Ji, Xiaoyu Hu, and colleagues at Tsinghua University, is among the strongest evidence in this whole story. Using genetic, genomic, metabolic, and immunological approaches, the team showed that creatine reprograms macrophage polarization, suppressing the interferon gamma driven, M1 style program while promoting the interleukin 4 driven, M2 style program. Mechanistically, creatine damped the JAK STAT1 signaling relay that interferon gamma uses, while supporting the interleukin 4 pathway through STAT6 and chromatin remodeling.

The transporter experiments settled which molecule deserves the credit. Creatine cannot simply drift into cells; it needs a dedicated transporter, called Slc6a8. Creatinine, by contrast, diffuses across membranes freely. As Drescher recounts, macrophages lacking the transporter lost the shift and skewed toward the inflammatory phenotype, showing the effect depends on creatine uptake itself rather than on its breakdown product, and removing the transporter altered macrophage driven immune responses in living animals. Put the pieces together and a consistent picture emerges from independent laboratories: creatine nudges innate immune cells away from attack posture and toward maintenance and repair.

Blood Vessels and Immune Cell Traffic

For inflammation to happen in a tissue, immune cells have to get there, and Drescher walks through the logistics. Resting macrophages sit quietly in healthy tissue. When they sense infection, they release signals such as TNF and interleukin 8 that change the character of the endothelium, the cell layer lining blood vessels. Adhesion molecules with names like ICAM and VCAM appear on the vessel wall. Passing neutrophils, the immune system’s shock troops, catch on these molecules, roll along the wall, and then squeeze between endothelial cells into the tissue, a step called diapedesis. TNF, in her description, changes the flavor of the endothelium so that all of this becomes possible.

A Japanese team led by Akihiro Nomura asked what creatine does to this traffic system, publishing the answer in the British Journal of Pharmacology in 2003. Working with cultured human pulmonary endothelial cells, they first confirmed that supplemented creatine enters the cells through the creatine transporter and raises intracellular creatine and phosphocreatine. Then came the functional tests. Creatine at 5 millimolar significantly suppressed the rise in endothelial permeability triggered by serotonin and by hydrogen peroxide, two well known leak inducing mediators, and it significantly reduced neutrophil adhesion to the endothelial layer. The team went further than the talk describes: creatine also inhibited expression of the adhesion molecules ICAM 1 and E selectin, an effect involving adenosine receptor signaling.

Drescher’s reading is straightforward. If fewer neutrophils leave the bloodstream and vessel walls stay sealed, less collateral inflammation reaches the tissue. It is tempting to connect this to sports science, where a 2022 review gathered evidence that creatine supplementation can decrease markers of inflammation, including a study reporting lower inflammatory cytokines and prostaglandin E2 in supplemented athletes after a half Ironman. Hold that thought, though, because the human evidence deserves its own honest accounting, and it comes at the end of this article.

The Allergy and Asthma Caveat

Not every study points the same direction, and Drescher spends real time on the one that points the other way. In 2007, Rodolfo Vieira and colleagues in São Paulo tested creatine in a mouse model of allergic asthma, noting that asthma is common among athletes, many of whom may be taking creatine. Balb/c mice were sensitized to ovalbumin, an egg protein that reliably provokes allergic airway disease, and given creatine at 0.5 grams per kilogram per day. The supplement made things worse. Creatine in the sensitized mice increased airway hyperresponsiveness and eosinophilic inflammation, raised the density of cells producing interleukin 4, interleukin 5, and insulin like growth factor 1, increased airway collagen and elastic fibers, and thickened airway smooth muscle. Those are the signatures of worsening asthma and airway remodeling.

Here is the apparent paradox: how can a compound that damps inflammation in every other experiment aggravate an inflammatory disease? The resolution is that inflammation is not one thing. Immune responses partition roughly into Th1 responses, aimed at microbes and driven by signals like interferon gamma and TNF through NF kappa B, and Th2 responses, aimed at parasites and responsible for allergy, driven by interleukin 4 and interleukin 5. Drescher notes that NF kappa B activation actually fell in the asthmatic mice, exactly what her own data would predict. Creatine appears to quiet the Th1 style machinery while feeding the Th2 style machinery, which fits the Immunity finding that creatine promotes the interleukin 4 driven macrophage program. Calming one arm of the immune system can mean amplifying the other.

Drescher urges caution before anyone concludes that creatine will worsen human allergies. The animals in these experiments belong to strains genetically primed for allergic disease. Most people, she says, run Th1 dominant under most conditions, and only a subset is strongly prone to allergic inflammation. For that subset, creatine may not be the best choice, but she stresses that this rests on a handful of mouse studies and needs far more research before firm statements about people are justified. The practical translation is modest: nothing here suggests a problem for typical healthy users, and a person with significant asthma or allergic disease has a reasonable topic to raise with their doctor before supplementing.

Sepsis, Autoimmunity, and Open Questions

The last part of the talk is openly speculative, and it should be read that way: these are research ideas, not treatment recommendations.

The first idea concerns septic shock, the catastrophic collapse that can follow severe infection, in which the immune response itself becomes the danger, with overactive TLR4 signaling near the center of the cascade. The genetics here is famous. In 1998, Bruce Beutler’s team showed that mouse strains carrying mutations in the Tlr4 gene are resistant to endotoxin, the LPS driven shock state, a discovery that helped earn Beutler a share of the 2011 Nobel Prize for work on the activation of innate immunity. Drescher’s question follows naturally from her data: if creatine turns down TLR4 expression and TNF output, could it serve as an inexpensive additional treatment, alongside standard care and never instead of it, to lower the odds of septic shock in someone with a severe infection? It is a testable idea, and only that. The same genetics carries a built in warning: the shock resistant mice were also highly susceptible to gram negative infection itself, because a dulled alarm system has costs. No human trial has examined creatine for sepsis.

The second idea concerns autoimmunity, which Drescher characterizes as a normal immune response that has spun out of control, with many autoimmune conditions strongly inflammatory in nature. She names rheumatoid arthritis and multiple sclerosis. TNF is a major contributor to the chronic inflammation that destroys joints in rheumatoid arthritis, which is precisely why TNF directed therapeutics became a pillar of treatment for TNF mediated diseases. Her thought experiment: could people genetically predisposed to such conditions take a safe, inexpensive agent that modestly reduces TNF before symptoms progress, and slow the damage? Even a modest reduction, she argues, might improve quality of life if it held up in humans. It has not been tested, and nothing in this article should be read as a reason to alter medical care.

She closes with the unknowns. Creatine’s other molecular targets, such as microRNAs and long noncoding RNAs, remain unexplored, and her group’s next step is animal models of inflammation. The immune story also extends beyond the innate system covered in the talk. Preclinical work summarized in a 2021 Nutrients review found that creatine serves as an energy reserve powering CD8 T cell activity against tumors, with supplementation improving tumor control in mouse models and synergizing with checkpoint inhibitor immunotherapy. Whether any of this translates to people is exactly the question the field must now answer.

What This Means for Creatine Users

Step back and the pattern is striking for its consistency across five decades and unrelated laboratories. Rats in the 1970s swelled less. Endothelial cells in 2003 leaked less and caught fewer neutrophils. Macrophages in 2011 dialed down their alarm receptors, in 2018 made less TNF, and in 2019 shifted from attack mode toward repair mode, an effect traced to creatine uptake itself. These findings agree with each other mechanistically, which is not nothing. But they are cell and animal findings, and the honest question for a supplement user is what happens in people.

Here the record is thinner and more sobering. Individual human studies have reported lower inflammatory markers with creatine, particularly around extreme endurance exercise, and reviewers have suggested these properties could help create a favorable environment for recovery. But in 2026, researchers in Brazil pooled the randomized, placebo controlled clinical trials that measured the most common inflammatory biomarkers, publishing in Frontiers in Immunology. Across eight randomized double blind trials in healthy people, athletes, and clinical populations, creatine produced no significant acute effect on C reactive protein and no significant chronic effect on C reactive protein or interleukin 6, with the certainty of evidence rated moderate. Their conclusion was blunt: on current evidence, creatine supplementation does not significantly reduce inflammatory biomarkers in humans. The authors frame this as a call for better trials rather than a closed door, noting how few clinical trials exist and urging the scientific community to advance the area. This is why the honest evidence rating for creatine as an immune or inflammation supplement is early: real mechanisms, consistent preclinical signals, unproven human benefit.

Safety, at least, is well mapped for ordinary use. The International Society of Sports Nutrition’s position stand concludes that creatine supplementation is safe and well tolerated in healthy individuals and in patient populations ranging from infants to the elderly, with studies covering intakes up to 30 grams per day for five years. Drescher’s own reassurance fits within that: the TLR effect she found was a partial, temporary turn down, not a disabling of immune sensing, and nothing in the literature suggests normal creatine use leaves people more vulnerable to infection. Her 2021 review still flags that immune specific data in children and older adults is limited, a gap worth remembering.

So the bottom line for a creatine user is unchanged in practice and more interesting in principle. Take creatine for what it is proven to do: strength, power, training adaptations, and recovery. Do not take it to treat or prevent infections, sepsis, or autoimmune disease, because no human evidence supports that, and serious conditions need medical care. If you have significant allergies or asthma, mention creatine to your clinician, since the mouse data, though limited, points in an unfavorable direction for allergy prone biology. And keep watching this field. The gym molecule turns out to have a second life in the immunology lab, and the next wave of animal and human studies will show whether that life matters outside the dish.